Abstract
Intravascular levels of low-density lipoprotein cholesterol (LDL-C) at approximately
≤ 0.6 mmol/L are likely to minimize, and perhaps eliminate, LDL-C-related vascular
toxicity while having no effect on essential, intracellular cholesterol homeostatic
pathways, according to accumulated knowledge from basic science. Randomized clinical
trials, observational reports, and Mendelian randomization trials are also forcing
a reconsideration of what “normal” LDL-C means. Recent trials of secondary prevention
have substantiated that such levels are safe and associated with a decreased risk
of cardiovascular events (CVEs) compared with patients with higher levels of LDL-C.
Similarly, treatment to this low range is associated with regression and stabilization
of established atherosclerosis. Primary prevention trials also show that low levels
of LDL-C are safe and associated with decreased risk of CVEs through cholesterol-lowering
in adults with LDL-C ≥ 3.5 mmol/L or when levels are < 3.5 mmol/L in association with
other cardiovascular risks. Although there are no randomized clinical outcome trials
of familial hypercholesterolemia patients, such patients have very high, lifetime
risk of CVE, and registry studies show that LDL-C reduction has nearly normalized
their CVE rates. The possibility of familial hypercholesterolemia should be considered
if LDL-C is > 4.5 and > 4.0 mmol/L at ages 18-39 years and younger than 18 years,
respectively. On the basis of these convergent and internally consistent lines of
evidence, in this article we speculate on a translational paradigm aimed at eliminating
LDL-C-related CVEs through aggressive primary prevention strategies that are already
proven and well accepted in principle.
Résumé
D’après les connaissances acquises dans le domaine des sciences fondamentales, les
concentrations intravasculaires de cholestérol à lipoprotéines de faible densité (C-LDL)
égales ou inférieures à environ 0,6 mmol/l sont de nature à réduire au minimum, voire
à éliminer la toxicité vasculaire liée au C-LDL tout en étant sans effet sur les voies
homéostatiques essentielles du cholestérol intracellulaire. Les essais cliniques à
répartition aléatoire, les rapports de cas clinique et les essais à randomisation
mendélienne amènent également à reconsidérer ce que signifie une concentration de
C-LDL « normale ». Les essais cliniques sur la prévention secondaire réalisés récemment
sont venus confirmer que de telles concentrations sont sans danger et sont associées
à une diminution du risque d'événement cardiovasculaire comparativement aux patients
présentant une concentration de C-LDL plus élevée. De même, le traitement visant l'atteinte
de cette plage de valeurs faibles est associé à la régression et à la stabilisation
de l'athérosclérose installée. Les essais cliniques sur la prévention primaire montrent
également que les faibles concentrations de C-LDL sont sans danger et associées à
une réduction du risque d'événements cardiovasculaires par l'intermédiaire de l'abaissement
du taux de cholestérol chez les adultes présentant un taux de C-LDL ≥ 3,5 mmol/l,
ou quand les valeurs sont < 3,5 mmol/l en association avec d'autres risques cardiovasculaires.
Aucun essai clinique à répartition aléatoire n’a été mené sur les effets chez les
patients atteints d'hypercholestérolémie familiale, mais on sait que ces individus
présentent un risque très élevé d'événements cardiovasculaires durant leur vie, et
les études fondées sur des registres montrent que la réduction du taux de C-LDL permet
pratiquement de normaliser la fréquence des événements cardiovasculaires dans cette
population. La possibilité d'une hypercholestérolémie familiale devrait être envisagée
si le taux de C-LDL est > 4,5 et > 4,0 mmol/l chez des patients âgés de 18 à 39 ans
et de moins de 18 ans, respectivement. Dans le présent article, nous nous appuyons
sur ces sources de données probantes convergentes et intrinsèquement cohérentes pour
réfléchir à un paradigme translationnel visant à éliminer les événements cardiovasculaires
liés au C-LDL par des stratégies de prévention primaire énergiques qui ont déjà fait
leurs preuves et dont le principe est bien accepté.
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Article info
Publication history
Published online: March 01, 2018
Accepted:
February 25,
2018
Received:
February 5,
2018
Footnotes
See page 550 for disclosure information.
Identification
Copyright
© 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
